Our laboratory uses biochemical, genetic, and transgenic methods to understand the normal and oncogenic properties of several genes implicated in neoplasia. Current activities address the following issues: (1) The functions of protein-tyrosine kinases. Members of two families of such kinases are currently under study: (a) Src, Hck, and other members of the Src family that have demonstrated functions in osteoclasts and fibroblasts from genetically altered mice, and (b) Rlk, a newly discovered member of the Btk/Itk family, expressed exclusively in T cells. (2) Multi-step carcinogenesis. (a) We have used MMTV-Wnt-1 transgenic mice to identify proto-oncogenes (members of the FGF family) and tumor suppressor genes (p53) that influence mammary tumorigenesis. We are also attempting to understand the roles of apoptosis, cell cycle control, genetic instability, and telomerase activity in p53-deficient tumors. (b) We are developing a new multi-step tumor model in transgenic mice by recapitulating the lesions found in human glioblastoma using a gene delivery system involving avian retroviral vectors. With this system, we can show that FGF promotes cell proliferation and migration and that a mutant EGF receptor initiates gliomagenesis. (3) Wnt gene signaling. We are studying the interactions between Wnt proteins and their newly-identified, seven-transmembrane receptors (Frizzled proteins). The roles played by these and several other proteins now implicated in Wnt signaling pathways are being examined in Xenopus and other mammalian systems. (4) p16, CDK4 and melanoma. We are cataloging and characterizing mutant forms of p16, an inhibitor of CDK/cyclin complexes, and of CDK4 that contribute to familial and sporadic melanomas. In addition, we are examining the newly discovered role of beta catenin, a component of the Wnt signaling pathway, in melanoma development.